The alternate designations for fatty acids used throughout the present specification, such as C2O:4.omega.6, refer to the total number of carbon atoms in the chain before the colon; the number of unsaturated bonds after the colon; and the number of carbon atoms from the end opposite the carboxylic acid at which the first unsaturation appears, following the omega .omega.. Members of a given omega series of fatty acids, e.g., .omega.-3, can usually be converted to acids of differing lengths and total number of unsaturations by normal body enzymes, but it is generally impossible to change a compound from one omega series to another, e.g., .omega.-3 to .omega.-6. This is because the enzymes generally cause changes of length and unsaturation to occur starting from the carboxylic acid end of the chain.
Arachidonic acid is stored in the membranes of the body as part of the phospholipids. The arachidonio acid is released from the phospholipids by the action of a phospholipase. The production of the phospholipase, which causes release of arachidonic acid, may be triggered by any one of a variety of mechanisms, including physical irritation and hypersensitivity. Once the arachidonic acid is released into the circulation, it may be oxidized by two different pathways. It is either metabolized by cyclo-oxygenase to produce prostaglandins, or by lipoxygenase to generate hydroperoxy derivatives which may be further metabolized to leucotrienes and SRS-A.
It has previously been theorized that SRS-A production can be inhibited by the inhibition of one or more of the enzymes required for its formation. For example, it is known that corticosteroids act to inhibit the phospholipase stage. Thus, the release of arachidonic acid is inhibited, causing the inhibition of the production of all of the metabolites of arachidonic acid, including the prostaglandins. Because of this, corticosteroids have been used as anti-inflammatories (for inhibition of prostaglandins) as well as anti-asthmatics (inhibition of SRS-A). Unfortunately, however, corticosteroids have severe and undesirable side effects.
Aspirin-like compounds and indomethacin inhibit only the cyclo-oxygenase pathway of arachidonic acid metabolism. Thus, these compounds can do nothing toward the treatment of asthmatic conditions and, in fact, giving aspirin to an asthmatic may provoke an attack because the aspirin forces SRS-A production by inhibiting the cyclo-oxygenase pathway of arachidonic acid.
Compounds which inhibit both the cyclo-oxygenase and lipoxygenase pathways for arachidonic acid metabolism can be expected to reduce SRS-A formation, but are also expected to have undesirable side effects due to the inhibition of the cyclo-oxygenase pathway, as, for example, the formation of stomach ulcers. Furthermore, substantially non-toxic natural substances which inhibit both cyclo-oxygenase and lipoxygenase are not known.
Another reason it is undesirable for an anti-asthmatic drug to inhibit cyclo-oxygenase is because cyclo-oxygenase is involved in the metabolism of PGE from dihomo-gamma-linolenic acid (C2O:6.omega.6), which is an important and desirable prostaglandin. PGEl interferes with the biosynthesis of cholesterol and endothelial cell proliferation.
There are a variety of lipoxygenases which oxidize various points of the arachidonic acid molecule. The lipoxygenase which catalyzes the production of SRS-A is the 5-lipoxygenase, which oxidizes the double bond of the 5-carbon atom or arachidonic acid. It is thus desirable specifically to inhibit 5-lipoxygenase, thus avoiding inhibition of other enzymes which produce products which are not necessarily undesirable.
The best drug for reduction of SRS-A and thereby for treatment of asthmatic attacks and bronchial spasms would be a specific 5-lipoxygenase inhibitor which does not inhibit cyclo-oxygenase or other lipoxygenases. Preferably, such a compound should be as nontoxic as possible.
Highly unsaturated fatty acids have been found to be particularly concentrated when there is a requirement for rapid movement at a cellular level such as may be required in transport mechanisms, for example, in the brain and its synaptic junctions, and the retina, where only the long-chain derivatives of the essential fatty acids are found, and not the parent linoleic and .alpha.-linolenic acids. The linoleic series can produce a docosapentaenoic acid (C2O:4.omega.6), but the main component used in cell membranes is arachidonic acid. In the .alpha.-linolenic series the main metabolite is docosaenoic acid. These long-chain derivatives are the principal components of cell structural lipids and also include the direct precursors for prostaglandins and leukotrienes.
The enzyme systems for the metabolism of fatty acids are, in general, shared. This means that the different fatty acids will compete with each other. It is known, for example, that saturated fats suppress the activity of essential fatty acid. If a part of the prostaglandin system is directly related to diet via metabolism of linoleic acid or can be controlled by using competing fatty acids such as eicosapentaenoic acid, it may be possible to take advantage of the competition that exists between the fatty acids for adjusting the desaturase, cyclo-oxygenase, or lipoxygenase enzyme systems.
Rubin, in U.S. Patent No. 4,584,320, discloses a composition for treating conditions caused by excessive release of SRS-A, consisting essentially of an amount effective to inhibit release of SRS-A of 8,11,14,17-eicosatetraenoic acid or a pharmaceutically acceptable salt or ester thereof in a pharmaceutically acceptable vehicle, and a method for the treatment of conditions caused by excessive release of SRS-A, comprising administering to a patient having such condition an amount of 8,11,14,17-eicosatetraenoic acid or a pharmaceutically acceptable salt or ester thereof effective to inhibit the release of SRS-A.
This compound is similar in structure to arachidonic acid but is not metabolized by the enzyme 5-lipoxygenase in SRS-A. This compound is thus a competitive inhibitor, reacting with 5-lipoxygenase instead of arachidonic acid, and thus preventing the production of SRS-A.
Evans et al., in Prostaglandins 29 (3): 431-441, 1985, disclose that eicosa-5,8,11,14-tetraynoic acid is known to strongly inhibit both 12-lipoxygenase and cyclo-oxygenase. Additionally, eicosa-4,7,10,13-tetraynoic and henicos-5,8,11,14-tetraynoic acids were found to inhibit platelet lipoxygenase but not cyclooxygenase. Additionally, eicosa-5,8,14-triynoic acid and eicosa-5,11,14-triynoic acids were found to inhibit cyclooxygenase but were inactive against lipoxygenase.
Reich et al., in Prostaolandins 26 (6): 1011-1020, 1983, disclose that 5,8,11-eicosatriynoic acid reduced the number of ova released from treated ovaries in a dose-dependent manner.
Wilhelm et al., in Prostaglandins 21 (2): 323-332, 1981, report that, of nine acetylenic acids examined, both 4,7,10,13-eicosatetraynoic acid and 5,8,11-14-henicosatetraynoic acid inhibit lipoxygenase more than 95 percent without any significant reduction in thromboxane B2 or HHT synthesis.
Sun et al., in Prostaolandins 21 (2): 333-343, 1981, disclose the inhibition of platelet arachidonic acid 12-lipoxygenase by acetylenic acid compounds including 4,7,10,13-eicosatetraynoic acid; 5,8,11,14eicosatetraynoic acid. L Goetz et al., in Prostaolandins 12 (2): 187-192, 1976, discloses that acetylenic acids inhibit prostaglandin synthesis from eicosa-8,11,14-trienoic acid in microsomes. Octadeca-6,9,12- triynoic acid and eicosa-8,11,14-triynoic acid were found to be the most potent inhibitors, the presence of an .omega.-8 methylene group being their commonality, although the presence of an .omega.-8 methylene group is not the only determinant of inhibitory potency.
Voorhees et al., in U.S. Patents 4,181,725 and 4,190,669, disclose that eicosa-5,8,11,14-tetraynoic acid or 5,8,11-eicosatriynoic acid can be used to treat psoriasis. In French patent 2 584 400, it is disclosed that esters and amides of eicosatriynoic acid can be used to treat inflammatory skin conditions such as psoriasis, eczema, acne, and the like.
Orning et al., in J. Biol. Chem. 255 (7): 8023-8026, 1980; disclose that 5,8,11-eicosatriynoic acid is a known lipoxygenase inhibitor, prevents the biosynthesis of leukotriene C4 by mastocytoma cells.
Evans et al., in Chemistry and Physics of Lipids 38: 327-342, 1985, disclose a method for synthesizing 5,8,14-icosatrienoic acid and 5, 11,14-icosatrienoic acid and their acetylenic analogues by hydrogen abstraction from a methylene carbon atom located at the center of a 1,4-ci pentadiene system.
Kunau et al., in Hoppe-Seyler's Z. Physiol. Chem. 352, pp 542-548, 1971, disclose a method for synthesizing polyynoic acids having four, five, and six triple bonds from alcohols already having triple bonds.
A number of .omega.-3 fatty acids having triple bonds at the 5- , 8-, and/or 11-position have been found to be useful in treating asthma, as disclosed in copending application Serial No. 07/276,467, Nov. 22, 1988, and incorporated herein by reference.